Insulin resistance plays a key role in the pathogenesis of type 2 diabetes, a disorder that affects 16 million people in the United States. Thus, elucidation of the factors that modulate insulin action has important public health implications. The relationship between androgens and insulin resistance in the human is complex with clear evidence of sexual dimorphism. In the female, insulin resistance is associated with hyperandrogenenism, while epidemiologic studies in the male consistently demonstrate an inverse relationship between testosterone and insulin. Current data on causality are conflicting. Therefore, the overall goat of this proposal is to define precisely the causal determinants of the inverse relationship between insulin resistance and testosterone in men. Specific aim 1 will determine if the abnormalities demonstrated in the hypothalamic-pituitary-gonadal axis of men with type 2 diabetes can be corrected by administration of an insulin sensitizing agent. Specific aim 2 will define the dose-response relationship between increasing testosterone and insulin resistance using two experimental human models: a) normal men after induction of hypogonadism with a GnRH antagonist and again after physiologic testosterone replacement; and b) men with congenital idiopathic hypogonadotropic hypogonadism before and after androgen replacement. Specific aim 3 will examine the impact of testosterone supplementation on insulin resistance and gtycemic control in men with type 2 diabetes. The selective and sequential manipulation of sex steroid and insulin levels as outlined in this proposal will permit precise definition of the relationship between testosterone and insulin resistance in men to be established and their causal determinants unequivocally defined. Given the significant cardiovascular morbidity and mortality associated with insulin resistant states such as obesity and type 2 diabetes, a clearer understanding of the interplay between testosterone and insulin resistance has important clinical significance and may potentially facilitate the development of new therapeutic strategies for these extremely common metabolic disorders.